Project Summary The heart has the remarkable capacity to adapt to metabolic, hormonal, and stress signals, in part by secreting factors that act in an autocrine/paracrine manner to optimize cardiac function. However, the endocrine function of the heart is a relatively new aspect of cardiac biology that is not fully understood. Dr. Kedryn Baskin is spear- heading investigations into the role of the heart in regulating systemic metabolism. We recently determined that ?lean factors? secreted by the heart regulate metabolism of extra-cardiac tissue. These findings suggest that identification and exploitation of cardiac-secreted factor(s) has therapeutic potential. The PI?s long-term goals are to identify secreted proteins and metabolites from the heart that have the potential to regulate systemic metabolism. Her short-term goals are to determine the metabolic functions of GBAS and KLK11. To accomplish these goals, the PI has performed proteomic analysis of secreted factors and screened them for their metabolic capacity. She has identified several ?lean factors? secreted from the heart (called cardiomyokines) that enhance metabolic rates. The PI will investigate GBAS and KLK11, two novel cardiomyokines that regulate metabolism. Aim 1 will determine how cardiac-secreted GBAS and KLK11 regulate systemic metabolism. Aim 2 will identify the roles of these proteins during exercise and will determine the protective effect of GBAS and KLK11 in the setting of obesity, and Aim 3 will determine the mechanisms by which this occurs. This application will provide the PI with the scientific training, mentoring, and career development necessary as she transitions to inde- pendence. The scientifically stimulating, and highly collaborative nature of UT Southwestern provides an envi- ronment that supports the development of young investigators. The PI will be mentored by Dr. Eric Olson and the members of the PI?s advisory committee, Drs. Philipp Scherer, Rhonda Bassel-Duby, Jeffrey McDonald, and Hamid Mirzae. The proposed research and career development plan will enable the PI to investigate the metabolic functions of GBAS and KLK11. She will continue to elucidate the functions of GBAS and KLK11, delv- ing into the mechanistic details of how GBAS and KLK11 regulate metabolism. Aims 1-3 will provide the scien- tific tools and training needed to successfully advance the burgeoning field of metabolically active secreted factors. Identification of cardiomyokines with metabolic signaling properties provides a foundation for the dis- covery of novel therapeutic targets for metabolic diseases.